In spite of remarkable progress in management of rheumatoid arthritis (RA), a devastating autoimmune disease that affects 2.5 million Americans causing chronic inflammation of joints and surrounding tissues, the gap of unmet needs in this therapeutic field remains wide open. First of all, almost 50% of the patients do not respond adequately to the most advanced mainstay treatment with the biologics, such as Remicade and Enbrel, that target individual pro-inflammatory cytokines. It is recognized that these therapeutic failures may be related to the functional redundancies within the cytokine network. Furthermore, the current RA medications act by suppressing multiple axes of immune response thereby markedly elevating risk of opportunistic infections. Both the relatively high cost of treatment and invasive (intravenous, subcutaneous or intra-articular) route of administration also contribute to the list of notable drawbacks for the standard-of-care RA biologics. A potential new strategy for the treatment of rheumatoid arthritis, which centers on maintaining vascular integrity with minimal overall immunosuppression, provides the rationale for the present project. The essential roles of vascular response in RA pathophysiology are well documented. Both disruption of vascular endothelial barrier and pathologic angiogenesis that are induced by pro-inflammatory stimuli including cytokines in synovial tissue play key roles in rheumatoid inflammation and destruction of joints. Our proposed signaling model suggests that inhibitors of small GTPase Arf6 would block vascular hyperpermeability and angiogenesis at a convergence point downstream from multiple pro-arthritic receptors while leaving the NF?B cascade, which governs other aspects of immune response, essentially intact. In our view, such a therapeutic approach may allow, first, to improve responsiveness to the treatment by overcoming the limitation associated with cytokine redundancies, and, second, to improve drug safety by minimizing immunosuppressive effects. The first in-class chemical series of small molecule Arf6 inhibitors identified in the Phase I SBIR study is proposed as a starting point for the medicinal chemistry-driven lead optimization program in Phase II. Its top representatives have been characterized by both cell barrier-stabilizing and anti-angiogenic activities in cellular models and, most importantly, by therapeutic efficacy comparable to that of Enbrel in a mouse model of collagen-induced arthritis. The proposed efforts are projected to yield orally bioavailable candidates for pre- clinical IND enabling studies with appropriate pharmacokinetic and toxicology profiles. The pharmacological modulation of Arf6 function may also have therapeutic potential in the context of other indications associated with vascular leak as evidenced by the promising outcome of preliminary efficacy studies using in vivo models of wet age-related macular degeneration and inflammation-induced acute lung injury.